PD-1 Blockade Alone Versus in Combination With Chemotherapy as First Line Therapy in Females With Advanced NSCLC & PD-L1 Expression ≥50%

Prior treatment

• No active disease in the last 5 years (requires PI approval) 13. Current or prior use of immunosuppressive medication within 14 days before first pembrolizumab dose.
  • Exceptions:
• Intranasal, inhaled, topical steroids, or local injections
• Systemic corticosteroids at doses ≤10 mg/day prednisone equivalent
• Steroids as premedication for hypersensitivity reactions 14. Treatment with systemic immunostimulatory agents (e.g., interferon, IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to study treatment.
  • 15\. Live vaccine within 30 days prior to first dose of study treatment. 16. Known allergy or hypersensitivity to any component of the chemotherapy regimen or pembrolizumab.
  • 17\. Any co-existing medical condition that, in the investigator's judgment, substantially increases risk associated with participation.
  • 18\. Pregnant or breastfeeding women. 19. Participant incarcerated or involuntarily institutionalized by court order or authorities.

Other illness

• Controlled Type I diabetes mellitus on insulin
• Chronic skin conditions not requiring systemic therapy

Lab values

• 1\. Mixed histology including any small-cell component. Participants with mixed non-small cell histology (e.g., squamous and non-squamous) may be eligible only if the predominant component (≥50%) is squamous cell carcinoma or adenocarcinoma.
  • 2\. Concurrent participation in another interventional clinical trial involving administration of an investigational medicinal product. Participation in non-interventional studies or registries is allowed.
  • 3\. Prior systemic treatment for metastatic or locally advanced disease or prior PD-1/PD-L1 immunotherapies (including CD137 agonists or immune checkpoint inhibitors such as anti-CTLA-4, anti-TIGIT, anti-PD-1, or anti-PD-L1 antibodies).
  • 4\. Concurrent radiotherapy for cancer treatment, except limited palliative radiotherapy for non-target lesions.
  • 5\. Candidate for complete surgical removal of oligometastatic disease; participants refusing surgery/ablations may be included.
  • 6\. Symptomatic or neurologically unstable CNS metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to study entry (maximum acceptable dose: ≤10 mg prednisolone).
  • 7\. Leptomeningeal disease. 8. History of interstitial lung disease. 9. Active infection requiring intravenous systemic therapy within 2 weeks prior to first study treatment. Participants with infections of CTCAE grade 1-2 that have been treated and clinically stabilized (e.g., uncomplicated urinary tract infection treated with oral antibiotics) may be included.
  • 10\. Known additional malignancy other than NSCLC, either untreated or requiring active treatment within the past 3 years.
  • 11\. Significant cardiovascular disease, including NYHA class ≥III congestive heart failure, clinically significant arrhythmias, or recent myocardial infarction (within 6 months). Left ventricular ejection fraction (LVEF) must be ≥50% (or ≥ institutional lower limit of normal) as assessed by echocardiogram or MUGA scan.
  • 12\. Active autoimmune disease or history of autoimmune or chronic inflammatory disorders requiring systemic treatment (e.g., corticosteroids, immunosuppressants) within the past 2 years, including but not limited to celiac disease, systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis.
  • Note: Diverticulitis is considered under this criterion only if recurrent or chronic; uncomplicated diverticulosis is allowed.
  • Exceptions:

Other

• Vitiligo or alopecia
• Hypothyroidism stable on hormone replacement

• Ability to understand the nature, significance, and individual consequences of the clinical trial.
• Written informed consent obtained prior to any trial-related procedures.
• Female participant aged ≥18 years at the time of signing the informed consent form.
• Histologically or cytologically confirmed stage IV NSCLC (squamous cell carcinoma or adenocarcinoma).
• Negative molecular testing for EGFR, ALK, and ROS1 alterations (tested locally).
• PD-L1 tumor proportion score (TPS) ≥50%, tested locally by QUiP®-certified immunohistochemistry.
• ECOG performance status ≤2.
• At least one measurable lesion according to RECIST v1.1.
• Adequate hepatic, renal, and bone marrow function, confirmed within 14 days prior to randomization:
  • Hematology (Hemoglobin ≥ 8.0 g/dL, Absolute neutrophil count (ANC) ≥ 2.0 × 10⁹/L, Total leukocyte count \> 4.0 × 10⁹/L, Platelet count ≥ 100 × 10⁹/L, Serum albumin ≥ 3.0 g/dL) Renal function (Calculated creatinine clearance ≥ 60 mL/min (CKD-EPI equation, Serum creatinine ≤ 1.5 × ULN, Blood urea nitrogen (BUN) ≤ ULN) Hepatic function (Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for participants with Gilbert's syndrome, AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present, Alkaline phosphatase ≤ 2.5 × ULN (≤ 5 × ULN if bone or liver metastases present Coagulation (INR and aPTT ≤ 1.5 × ULN unless on anticoagulant therapy (values within therapeutic range allowed)
• Female participants of childbearing potential (WOCBP) must use a highly effective contraceptive method (failure rate \<1% per year) during treatment and for 6 months after the last dose. Participants who are postmenopausal or surgically sterile do not require contraception.